Aberrant Activation Mechanism of TGF-β Signaling in Epithelial-mesenchymal Transition

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  • Yuki Ryuzaburo
    Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University

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  • 上皮間葉転換を司るTGF-βシグナルの過剰活性化機構の解明
  • ジョウヒ カンヨウ テンカン オ ツカサドル TGF-vシグナル ノ カジョウ カッセイカ キコウ ノ カイメイ

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Abstract

<p>Epithelial-mesenchymal transition (EMT) is an important program in epithelial cancer cells to acquire the motility and invasion, which promotes cancer metastasis to remote organs. EMT is induced by various secreted factors, such as transforming growth factor-β (TGF-β) and epidermal growth factor (EGF). TGF-β ligand activates Smad-dependent and -independent pathways by binding to TGF-β receptors. In Smad-dependent pathway, the activated TGF-β receptor phosphorylates Smad2/3 and accelerates its association with Smad4, leading to their nuclear translocation. Smad2/3-4 complex promotes the expression of EMT-inducing transcription factors, such as Snail and Slug. In Smad-independent pathway, mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are activated and required for TGF-β-induced EMT. Smad-independent pathway is similar to downstream of receptor tyrosine kinases, and therefore EGFR signaling is known to induce EMT synergize with TGF-β signaling. We explored a new mechanism of EGFR-mediated activation of TGF-β signaling and found that c-Abl kinase activates TGF-β signaling. Based on our proteomic analysis, we identified several TGF-β signaling molecules as nuclear c-Abl substrates, including transcriptional intermediary factor 1-γ (TIF1γ/TRIM33/Ectodermin), a suppressor of TGF-β signaling. c-Abl-mediated phosphorylation of TIF1γ inhibits its binding to Smad3, thereby increasing Smad3's transcriptional activity and promoting EMT. TIF1γ phosphorylation is also involved in the EGFR-caused aberrant activation of TGF-β signaling, suggesting that EGFR/c-Abl pathway activates TGF-β signaling through phosphorylation of nuclear substrates and promotes EMT. Our findings provide new insights into the activation machinery of TGF-β signaling, and further studies are required to clarify the clinical significance of the EGFR/c-Abl pathway in cancer metastasis.</p>

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  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 141 (11), 1229-1234, 2021-11-01

    The Pharmaceutical Society of Japan

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